Islet Transplantation Using Abatacept

This study has been completed.
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Nicole Turgeon MD, Emory University
ClinicalTrials.gov Identifier:
NCT00276250
First received: January 12, 2006
Last updated: June 16, 2016
Last verified: June 2016
  Purpose
Islet transplantation in type 1 diabetics with hypoglycemic unawareness using abatacept as a part of a novel calcineurin-inhibitor-sparing immunosuppressive regimen.

Condition Intervention Phase
Type 1 Diabetes Mellitus
Drug: Efalizumab
Drug: Abatacept
Drug: Belatacept
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Development of Immunosuppression Regimens to Facilitate Single Donor Islet Transplantation Using Abatacept

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • The Number of Insulin-independent Subjects at Day 75 (± 5 Days) Following the First Islet Cell Transplantation [ Time Frame: 75 days post-transplantation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of Insulin-independent Subjects Following Islet Transplantation [ Time Frame: 1, 3, 6, 9,12,18 and 24 months post-transplantation ] [ Designated as safety issue: No ]
    Participants who did not need to take insulin at 1, 3, 6, 9, 12, 18, and 24 months following islet transplantation

  • Number of Subjects With HbA1C Less Than 6.5% [ Time Frame: 6 months post-transplantation ] [ Designated as safety issue: No ]
    HbA1C was assessed in the subjects 6 months after transplantation and the number of subjects with values less than 6.5% was recorded which indicated better control of blood glucose levels.

  • Number of Subjects With HbA1C Levels < 6.5% [ Time Frame: 12 months post-transplantation ] [ Designated as safety issue: No ]
    HbA1C was assessed in the subjects 12 months after transplantation and the number of subjects with levels < 6.5% was recorded which indicated better control of blood glucose levels.

  • Number of Subjects With HbA1C < 6.5% [ Time Frame: 24 months post-transplant ] [ Designated as safety issue: No ]
    HbA1C was assessed in the subjects 24 months after transplantation and the number of subjects with levels < 6.5% was recorded which indicated better control of blood glucose levels.

  • Number of Subjects With HbA1C < 6.5% [ Time Frame: 36 months post-transplantation ] [ Designated as safety issue: No ]
    HbA1C was assessed in the subjects 36 months after transplantation and the number of subjects with values < 6.5% was recorded which indicated better control of blood glucose levels.

  • Number of Participants With Endogenous Insulin Production Post-transplant, Assessed by Fasting C-peptide Levels [ Time Frame: 1, 3, 6, 9,12,18 and 24 months post-transplantation ] [ Designated as safety issue: No ]
    The number of subjects exhibiting C-peptide levels ≥ 0.5 ng/mL was recorded.

  • The Number of Study Participants Exhibiting a Successful Response to a Standard Mixed Meal Test, Measured by Stimulated C-peptide Levels After Islet Transplant. [ Time Frame: 1, 3, 6, 9,12,18 and 24 months post-transplantation ] [ Designated as safety issue: No ]
    The number of study participants who have detectable C-peptide levels after stimulation from a Mixed Meal Test. An increase of C-peptide indicates that insulin is being released normally in response to food consumption.

  • Number of Subjects With Normal Renal Function, as Measured by Serum Creatinine Levels [ Time Frame: 24 months after transplant ] [ Designated as safety issue: No ]
    Renal function was assessed by measuring levels of serum creatinine. Normal values range from 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women.


Enrollment: 5
Study Start Date: December 2005
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Efalizumab Followed by Abatacept Regimen
Participants with Type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years received efalizumab-based immunosuppression regimen after islet-cell transplantation. During the course of the study, efalizumab was withdrawn from the US market due to safety concerns. The protocol was subsequently amended to alter the immunosuppressive regimen to abatacept for these participants.
Drug: Efalizumab
Efalizumab was a medication approved for use in psoriasis which was being explored to determine efficacy with immunosuppression following organ transplantation. Efalizumab was administered subcutaneously on a weekly basis. Upon efalizumab being withdrawn from the US market, the protocol was amended to alter the immunosuppressive regimen to abatacept for the study participants.
Other Name: Raptiva
Drug: Abatacept
Abatacept is drug used to treat autoimmune diseases. Abatacept is administered intravenously, monthly, in weight-based doses and is given for as long as transplanted islets are functioning.
Other Name: Orencia
Experimental: Abatacept Regimen
Participants with Type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years received abatacept immunosuppresion regimen after islet-cell transplantation.
Drug: Abatacept
Abatacept is drug used to treat autoimmune diseases. Abatacept is administered intravenously, monthly, in weight-based doses and is given for as long as transplanted islets are functioning.
Other Name: Orencia
Experimental: Belatacept Regimen
Participants with Type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years received Belatacept immunosuppresion regimen after islet-cell transplantation.
Drug: Belatacept
Belatacept is a medication to provide extended graft survival while limiting the toxicity generated by standard immune suppressing regimens. Belatacept is administered intravenously. The protocol for this study was amended to substitute belatacept for abatacept for all newly enrolling participants (current participants remained on abatacept).
Other Name: Nulojix

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  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and Female patients age 18 to 65 years of age
  • Clinical history compatible with type 1 diabetes with onset of disease at <40 years of age and insulin-dependence for >5 years at the time of enrollment.
  • Body mass index less than or equal to 26
  • 18 to 65 years of age
  • Absent stimulated C-peptide (<0.3ng/ml) in response to a mixed meal tolerance test (Boost® 6 mL/kg body weight to a maximum of 360 mL; another product with equivalent caloric and nutrient content may be substituted for Boost) measured at 90min after the end of consumption.
  • Compliance with an optimized diabetic management plan as assessed by an Emory University endocrinologist
  • Checking and recording blood sugars at least 3 times per day
  • Involvement in intensive diabetes management defined as self monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the previous 12 months.
  • At least one episode of severe hypoglycemia in the past 3 years defined as an event with symptoms compatible with hypoglycemia in which the subject required the assistance of another person and which was associated with either a blood glucose level <50 mg/dL [2.8 mmol/L] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration).
  • Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more and a HYPO score greater than or equal to the 90th percentile (1047) within the last 6 months prior to randomization; OR Marked glycemic lability characterized by wide swings in blood glucose despite optimal diabetes therapy and defined by a glycemic lability index (LI) score greater than or equal to the 90th percentile (433 mM2/h/wk) within the last 6 months prior to randomization; OR A composite of a Clarke score of 4 or more and a HYPO score greater than or equal to the 75th percentile (423) and a LI greater than of equal to the 75th percentile (329) within the last 6 months prior to randomization.

Exclusion Criteria:

  • Severe co-existing cardiac disease, characterized by any one of these conditions:
  • Recent myocardial infarction (within past six months)
  • Left Ventricular Ejection Fraction < 30%
  • Evidence of ischemia on a functional echocardiogram
  • Active infection including hepatitis B, hepatitis C, HIV, or TB as determined by a positive skin test or clinical presentation, or under treatment for suspected TB. Positive tests are acceptable only if associated with a history of previous vaccination in the absence of any sign of active infection. Positive tests are otherwise not acceptable, even in the absence of any active infection at the time of evaluation
  • Invasive aspergillus infection within one year prior to study entry.
  • Negative screen for Epstein-Barr Virus (EBV) by IgG determination.
  • Administration of live vaccine within the past two months
  • Measured glomerular filtration rate using iohexol <70 mL/min/1.73 m2 for females and <80 mL/min/1.73 m2 for males (or a 24 hr. creatinine clearance with participants allergic to iodine <85mL/min/1.73m2).
  • Macroalbuminuria (urinary protein excretion rate >300 mg/24h)
  • Baseline Hgb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/L), neutropenia (<1,500/L), or thrombocytopenia (platelets <100,000/ L).
  • Hyperlipidemia (fasting LDL cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >300 mg/dL)
  • Negative antibody test for Varicella zoster virus (subjects may be reconsidered if they receive the vaccination and convert to a positive antibody)
  • History of malignancy (except squamous or basal cell skin carcinoma) within the previous 5 years
  • Previous/concurrent organ transplantation
  • Presence of HLA Panel Reactive Antibodies >20%
  • Active peptic ulcer disease
  • Evidence of gallbladder disease including cholecystitis and cholelithiasis
  • Evidence of liver disease including: hepatic neoplasm, portal hypertension, or persistently abnormal liver function tests
  • Current use of systemic steroid medications
  • Evidence of insulin resistance (insulin requirements >0.8 units/kg/day)
  • Inability to provide informed consent
  • Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
  • Hyperlipidemia despite medical therapy (fasting LDL cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >200 mg/dL).
  • Acute or chronic pancreatitis.
  • Symptomatic peptic ulcer disease.
  • Use of any other investigational agents within 4 weeks of participation.
  • Any condition or any circumstance that makes it unsafe to undergo an islet cell transplant
  • Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients with an INR >1.5.
  • Sickle Cell Anemia (Subjects with Sickle Cell Anemia, trait HbSS, are at high risk for complications after transplantation related to immunosuppressive therapy. These complications include stroke and sickle cell crisis. Therefore, we will exclude these subjects from our study to minimize risks to study subjects.)
  • For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 3 months after discontinuation. For male participants: intent to procreate during the duration of the study or within 3 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
  • Active alcohol or substance abuse. This includes cigarette smoking (must be abstinent for six months). Active alcohol abuse should be considered using the current NIAAA definitions, whereby alcohol abuse is defined by a pattern of drinking that is accompanied by one or more of the following situations within a 12-month period:
  • Failure to fulfill major work, school, or home responsibilities
  • Drinking in situations that are physically dangerous, such as while driving a car or operating machinery
  • Recurring alcohol-related legal problems, such as driving under the influence of alcohol or for causing physical harm to someone while intoxicated
  • Continued alcohol abuse despite having ongoing relationship problems that are caused or worsened by the effects of alcohol
  • Psychiatric disorder making the subject not a suitable candidate for transplantation, e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication. (A psychological or psychiatric consultation is required only if considered necessary by some current indication or history.)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00276250

Locations
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Juvenile Diabetes Research Foundation
Investigators
Principal Investigator: Christian P Larsen, MD, D.Phil Emory University
Principal Investigator: Thomas C Pearson, MD, D,Phil Emory University
Study Director: Sallie C Carpentier, RN, BSN Emory University
Principal Investigator: Nicole Turgeon, MD Emory University
  More Information

Responsible Party: Nicole Turgeon MD, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT00276250     History of Changes
Other Study ID Numbers: IRB00021852  1136-2005 
Study First Received: January 12, 2006
Results First Received: April 25, 2016
Last Updated: June 16, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Abatacept
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 29, 2016